Is SETD1A p.Arg253Ter (c.757C>T) pathogenic?

SETD1A p.Arg253Ter (c.757C>T) is classified Pathogenic in SETD1A (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 0.00134%, afr); Associated with schizophrenia.

What condition is associated with SETD1A p.Arg253Ter (c.757C>T)?

SETD1A p.Arg253Ter (c.757C>T) is associated with schizophrenia (ClinVar).

How common is SETD1A p.Arg253Ter (c.757C>T) in the general population?

SETD1A p.Arg253Ter (c.757C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

SETD1A p.Arg253Ter

c.757C>T · rs2056099559 · VCV1330308

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

schizophrenia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 6 of 19
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,896 alleles

Overall 0.000124% 2/1,613,986 alleles · very rare exomes 1/1,461,864 · genomes 1/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,896
European (non-Finnish)	8.47e-05%	1,179,988

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETD1A
Protein: p.Arg253Ter
Coding: c.757C>T
MANE Select: NM_014712
dbSNP: rs2056099559
Type: single nucleotide variant
Location: chr16:30964211 (GRCh38)
Gene constraint: LOEUF 0.279 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 49.20 · 4 PDB
Residue 253: a UniProt-annotated variant site (in nedsid); the 'disordered' region

Full SETD1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

schizophrenia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1A p.Arg253Gln Uncertain significance ★ ⚠ same residue
SETD1A c.518-2A>G Pathogenic ★★ same condition
SETD1A p.Tyr646Ter Pathogenic ★★ same condition
SETD1A p.Gln737Ter Pathogenic ★ same condition
SETD1A p.Ala725fs Pathogenic ★ same condition
SETD1A p.Tyr425fs Pathogenic ★ same condition
SETD1A p.Arg1571Ter Pathogenic/Likely pathogenic ★★ same type
SETD1A p.Arg176Ter Pathogenic/Likely pathogenic ★★ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/setd1a-p-arg253ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown